Theneurotransmitterserotoninisthoughttohavebroadfunctionsinthecentral nervoussystem,contributingtothebiologicalbasisunderlyingbothbehaviorand cognition.Thisneurotransmitterhasalsobeenimplicatedinmentaldisorders, especiallyanxietyanddepression,andseveralpharmacologicalagentsusedtotreat thesediseasestargetserotonergicsystemsinthebrain. Serotoninactsthroughmultipleserotoninreceptorstoregulateneuronalactivityand workduringthelastdecadehasmadeextraordinaryadvancesinourunderstandingof thebasicbiologyofthesereceptors.Howeverourunderstandingofhowthesereceptors functionwithinneurons,whattheysignalandhowtheysignalinthecentralnervous system,isstillpoorlyunderstood.Thisisanimportantlacunae,sincethebiological basisofmentaldisorders,aswellasthedevelopmentofbettertreatments,willbe groundedinthespecificmechanismsusedbythesereceptors. ThelongtermgoalofthePI'sresearchprogramistohelpdevelopamechanistic understanding,atthemolecularlevel,ofserotoninreceptorfunctionincentralnervous systemneurons.Specificallyinthisapplicationweproposetouseasynergistic combinationofelectrophysiologicalandmolecularbiologicalapproachestounderstand thesignalingmechanismsusedby5 HT2Areceptorsinthecerebralcortex. TheapplicationproposesthreeSpecificAims.Thefirstofthesewillelucidatethe proximalsignalingmechanismusedby5 HT2Areceptorstoregulatemembrane excitabilityinpyramidalcellsoftheprefrontalcortex.ThesecondAimwilltesttheidea that5 HT2Areceptorsinhibittheslowcalcium activatedpotassiumcurrentpresentin pyramidalcellsbyreducingtheconcentrationofmembranePtdIns(4,5)2.Thethird SpecificAimwilldeterminehow5 HT2Areceptorsdepolarizeandexcitepyramidal cells. Theresultsofthisprojectshouldcontributetoourunderstandingofserotonergic mechanismsinthebrainand,assuch,contributetoourunderstandingofmental disorderswhilesupportingthesearchformoreeffectivetreatments. Theneurotransmitterserotoninhasbeenimplicatedinthegenesisofanxietyand depressionandinthemechanismofactionofseveraldrugseffectiveinthetreatmentof mentaldisorders.Theresearchproposedinthisapplicationseekstoelucidatethe molecularmechanismsusedbyserotonintoregulatethefunctionofbraincellsand braincircuits.Theresultsofthisprojectshouldhelpusbetterunderstandmental disordersandcontributetothesearchofmoreeffectivetreatments.